The Journal of Experimental Medicine
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Published online 28 February 2005 doi:10.1084/jem.20041854
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 5, 817-828
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ARTICLE

 An immunoglobulin C{kappa}-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system

Djemel Ait-Azzouzene1, Laurent Verkoczy1, Jorieke Peters1, Amanda Gavin1, Patrick Skog1, José Luis Vela1,2, and David Nemazee1

1 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
2 Kellogg School of Science and Technology Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA 92037

CORRESPONDENCE David Nemazee: nemazee{at}scripps.edu

Understanding immune tolerance mechanisms is a major goal of immunology research, but mechanistic studies have generally required the use of mouse models carrying untargeted or targeted antigen receptor transgenes, which distort lymphocyte development and therefore preclude analysis of a truly normal immune system. Here we demonstrate an advance in in vivo analysis of immune tolerance that overcomes these shortcomings. We show that custom superantigens generated by single chain antibody technology permit the study of tolerance in a normal, polyclonal immune system. In the present study we generated a membrane-tethered anti-Ig{kappa}–reactive single chain antibody chimeric gene and expressed it as a transgene in mice. B cell tolerance was directly characterized in the transgenic mice and in radiation bone marrow chimeras in which ligand-bearing mice served as recipients of nontransgenic cells. We find that the ubiquitously expressed, Ig{kappa}-reactive ligand induces efficient B cell tolerance primarily or exclusively by receptor editing. We also demonstrate the unique advantages of our model in the genetic and cellular analysis of immune tolerance.

Abbreviations used: RAG, recombinase activator gene; RS, recombining sequence.

J. Peters' present address is University Medical Centre, St. Radboud, Nijmegen University, 6500 HB Nijmegen, Netherlands.


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